With the rise in antibiotic resistance, the need for developing new antibiotics is becoming increasingly urgent. Phosphonate compounds are a promising class of anti-infective agents that mimic native phosphate substrates to inhibit essential enzymes found in viruses, tumors, and parasites, but are absent in mammals. Fosmidomycin is a phosphonate natural product that inhibits 1-deoxy-D-xylulose 5-phosphate reductoisomerase (IspC), a key enzyme in the non-mevalonate pathway found in many pathogens. Despite the therapeutic promise of these compounds, their use in medicine is often limited by permeability issues associated with their negative charge. To address this issue, we have synthesized a siderophore-IspC-inhibitor conjugate using an α-phenyl-substituted reverse fosmidomycin analog. Siderophore-antibiotic conjugates have been shown to increase the accumulation of antibiotics in bacteria using a trojan-horse strategy, whereby the siderophore complexes with ferric iron and allows for the transport of the sideromycin into the cell. Here, we evaluate sideromycins in improving accumulation and whole-cell activity of fosmidomycin analogs in bacteria.

Synthesis of siderophore-IspC-inhibitor conjugates

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